"The primary interest of our research is unraveling the pathogenesis of polycystic kidney disease. To this end, they have used positional cloning to identify the second gene for human autosomal dominant polycystic kidney disease (PKD2). The current proposal centers on the hypothesis that genetically altering the murine homologue of the PKD2 gene, Pkd2, will enable us to produce animal models whose phenotypes are faithful to those of human autosomal dominant polycystic kidney disease (ADPKD). They have produced a mouse line with a targeted mutation in which the first coding exon of Pkd2 has been disrupted. Mice heterozygous and homozygous for this allele develop polycystic kidneys and livers that recapitulate the human disease phenotype. The disease develops faster in homozygotes. They propose histopathological and functional characterization of the renal and extra-renal phenotypes of these mutant mouse lines as well as further analysis of the molecular consequences of the gene targeting event. This murine model of ADPKD has some residual polycystin-2 expression in the homozygous state. They propose to create a model in which exons 1, 2, and 3 of Pkd2 have been deleted. These null mice will provide a model system for studying the phenotype. In addition, they propose to introduce naturally occurring premature termination codons found in human families with ADPKD, into Pkd2. They will characterize the ensuing mouse phenotypes in heterozygous and homozygous mice and will characterize the functional consequences, at the level of the protein product, of these truncating mutations. Finally, they plan to study the effects of factors other than germ line mutation in Pkd2 on the occurrence and progression of the renal and extrarenal manifestations in mouse models of ADPKD. They will use marker assisted breeding strategies to produce congenic strains bearing mutations in Pkd2 on different genetic backgrounds. They will investigate the effects of defects in DNA mismatch repair on the progression of ADPKD by breeding Pkd2 mutations onto a MLH1-deficient mouse line."